Dizeez: All Fun and Games!

Researchers from the Scripps Research Institute have developed an online game that can give clues to gene-disease associations. Gene annotation, or the attachment of biological information about genes to sequences in genomic databases, currently lags far behind the ability to generate sequence data in the first place. There are several bottlenecks in the process, not the least of which is the generation of biological information. But one bottleneck is also curation, that is, the process of attaching known biological information to existing genome sequences. In their game, the authors had players choose which of five different genes was associated with a given disease. The authors found that roughly 80 percent of genes with the highest number of "votes" had evidence for a gene-disease association that had not yet made it into the annotated database. Unlike the game Foldit, Dizeez does require players to have expert knowledge. But the authors said that "these early results provide a basic proof of principle that online games can be successfully applied to the challenge of gene annotation." The study appeared in the Aug. 7, 2013, issue of PLoS ONE.

Another Chance for COX2 Inhibitors?

Researchers at Vanderbilt University have identified a way to specifically inhibit the effects of cyclooxygenase 2 (COX2) on endocannabinoid activity, which may open up a new path to the treatment of anxiety. COX2 inactivates endocannabinoids, but the therapeutic possibilities of that inactivation are complicated by COX2's effects on prostaglandin synthesis, which puts patients taking COX2 inhibitors at risk of cardiovascular problems – as the makers of Vioxx (rofecoxib, Merck & Co. Inc.), Celebrex (celecoxib, Pfizer Inc.) and Bextra (valdecoxib, Pfizer Inc.) have learned. In their studies, the authors developed a compound that affected specifically COX2's effects on endocannabinoids. Animals treated with the compound showed reduced anxiety. The authors said that "additional research will be required to evaluate the side effects of SSCIs relative to those of traditional COX inhibitors," but expressed hope that their compound's lack of an effect on prostaglandin synthesis will translate into both a reduced risk of gastrointestinal and cardiovascular side effects. Their findings appeared in the Aug. 4, 2013, online issue of Nature Neuroscience.

Autonomic Dysreflexia: The Other AD

Spinal cord injury can lead to an unexpected consequence, namely suppressed immunity. Now, scientists from Ohio State University reported that such immune suppression is caused by another consequence of spinal cord injury, namely autonomic dysreflexia, or hyperactive autonomic nervous system responses as the spinal autonomic nervous system is cut off from its higher-level inhibition. The authors showed they could induce immune suppression directly by activating the spinal autonomic nervous system, and such activation was due to the abnormal release of the neurotransmitter norepinephrine, and glucocorticoid hormones. They concluded that "these data implicate [autonomic dysreflexia] as a cause of secondary immune deficiency after [spinal cord injury] and reveal novel therapeutic targets for overcoming infectious complications that arise due to deficits in immune function." The findings appeared in the Aug. 7, 2013, issue of the Journal of Neuroscience.

Decoiling Enzyme Has Role in Mental Disorders

Separate teams, one from the University of California at Los Angeles and the German University of Wuerzburg and another from the National Institutes of Health have implicated mutations in the enzyme topoisomerase 3beta in multiple mental disorders. Topoisomerases basically serve to keep long DNA and RNA strands from turning into dysfunctional knots, and topoisomerase 3beta also interacts with the protein that is behind the autism spectrum disorder Fragile X syndrome, the Fragile X Mental Retardation Protein (FMRP). One group looked at the cell biology of the interaction and showed that mutations in FMRP that disturb its interaction with topoisomerase 3beta affect synapse formation. The other group, taking a population genetics approach, showed that genetically fairly isolated populations in Finland that have high rates of mutations in the topoisomerase 3beta genes are also at high risk for schizophrenia and cognitive impairment. The papers appeared back-to-back in the Aug. 4, 2013, online issue of Nature Neuroscience.

Promoting Autoimmunity, of a Sort

Graft-vs.-host disease (GvHD) is a dreaded complication of bone marrow transplants, but for cancer patients, one specific form of GvHD can be useful – namely, graft-vs.-leukemia disease, in which transplanted bone marrow attacks residual leukemia cells after a bone marrow transplant. Now, researchers from the Dana-Farber Cancer Institute have found that inducing graft-vs.-leukemia disease by vaccinating leukemia patients with their own killed tumor cells appears to help them control their disease. The authors tested their approach in 22 patients who had received a bone marrow transplant, vaccinating them with whole tumor cells mixed with other cells meant to increase the immune system's response. They found that vaccination induced T cells to multiple tumor antigens. The authors said their study suggested that whole-cell vaccination could help patients control their tumors, and more generally, that it "adds to a growing body of clinical studies that established safety, feasibility, and biological activity of whole tumor cell-based vaccination for patients with hematologic malignancies." The work appeared in the Aug. 5, 2013, issue of the Journal of Clinical Investigation.

And Never the Twain Shall Meet, if You're Lucky

Researchers at the University of California, San Diego School of Medicine have gained new insights into how amyloid precursor protein (APP) is kept away from BACE1, the enzyme that cleaves it into beta-amyloid. Given that both APP and BACE1 are highly expressed in the brain, it is in some ways surprising that Alzheimer's disease is not a universal part of the human condition. In cell culture studies, the authors found that BACE1 was usually found in more acidic endosomes, while APP's preferred location was transported in Golgi vesicles. However, neural activity – which triggers amyloid formation – could route BACE1-containing endosomes into APP-containing Golgi vesicles. The authors "speculate that sporadic [Alzheimer's disease] pathology results from the breakdown of such well-orchestrated trafficking pathways." Their findings were published in the Aug. 8, 2013, issue of Neuron.

Once We Have Vaccine, Might Make Good Adjuvant

Scientists at the University of Texas Southwestern Medical Center identified an enzyme that is an early sensor of infection with retroviruses, of which HIV is the deadliest member. How the innate immune system senses retroviral infection in its earliest stages has been unclear, and some researchers have argued that retroviruses in fact manage to avoid alerting the innate immune system altogether. In their work, the authors showed that retroviral infection does trigger the innate immune system through an enzyme called cGAS, which induces the production of a molecule called cGAMP and, ultimately, Type I interferons and other cytokines. cGAS is triggered by the production of DNA off of the retroviral RNA, and cells lacking cGAS did not produce cytokines in response to retroviral infection. The authors suggested that cGAMP "could be a candidate vaccine adjuvant for HIV and other pathogens that are adept at subverting the host innate immune system." Their findings were published in the Aug. 8, 2013, advance online edition of Science.

Upping the Ante on H7N9 Research

Researchers from the Dutch Erasmus Medical Center, the University of Wisconsin and other institutions have published correspondence indicating their intent to perform so-called gain-of-function research on the H7N9 strain of influenza. The strain has been the newest addition to the pandemic panic panoply, with roughly 130 cases, but a death rate of more than 20 percent. Scientists and public health officials alike suspect that H7N9 will return as winter, when flu viruses tend to emerge, arrives in the Northern hemisphere, and hope to understand the strain better. Gain-of-function research is controversial because it can result in exactly the sort of strain that could lead to a bad pandemic if it were to be accidentally – or purposefully released – but the researchers argued that the potential benefits of such research outweigh the risks, and officials at the National Institutes of Health and the Centers for Disease Control and Prevention agreed in separate correspondence. The correspondence was published in the Aug. 8, 2013, issue of Nature and the Aug. 9, 2013, issue of Science.

. . . For Good Reason

Meanwhile, scientists at the Chinese Jiangsu Provincial Center for Disease Control and Prevention reported that one case of H7N9 infection was probably transmitted from person to person, which is one key prerequisite for an influenza virus to become a pandemic threat. Most cases of H7N9 infection have been due to direct contact with poultry, but in their case report, the authors described a woman who appears to have been infected while caring for her father, who himself picked up the infection from poultry. The authors concluded that "the infection of the daughter probably resulted from contact with her father (the index patient) during unprotected exposure, suggesting that in this cluster the virus was able to transmit from person to person," though they also noted that "the transmissibility was limited and non-sustainable." Their work appeared in the Aug. 6, 2013, issue of the British Medical Journal.

Why Sunburn Hurts

A team from Rockefeller University, the University of California at San Francisco and Duke University has identified the ion channel TRPV4 as the signaling pathway that leads from UVB radiation to sunburn pain. In their work the authors found that mice lacking the TRPV4 channel only in the outermost layer of skin or epidermis had less tissue damage as well as less pain when they were exposed to UVB light. Sunburn is the skin's way of telling the body to get out of the sun, which causes major tissue damage on overexposure, but the pain from sunburn shares many features with chronic pain, which makes the model useful beyond sunburn. The findings appeared in the Aug. 5, 2013, online issue of the Proceedings of the National Academy of Sciences.

– Anette Breindl, Science Editor